Introducing functionality into unactivated C—H bonds remains a significant challenge both in the realm of complex molecule synthesis as well as in the elaboration of simple hydrocarbon feedstocks into value-added commodity chemicals (Bergman, Nature 2007, 446, 391; Labinger et al., Nature 2002, 417, 507). A challenge to the development of a general and mild aliphatic C—H bond functionalization strategy is the unreactive nature of the substrates themselves. Saturated hydrocarbons are chemically inert due to the large C—H bond dissociation energy (BDE, 93-105 kcal/mol) coupled with the energetic and spatial inaccessibility of the C—H bonding and antibonding orbitals. C—H bond activation processes are only realized under forcing conditions (Labinger et al., Nature 2002, 417, 507) or when directing functionalities pre-organize a substrate to interact with transition metal based catalysts (Ryabov, Chem. Rev. 90, 403 (1990); Dick et al., Tetrahedron 62, 2439 (2006)). Although the C—H bonds of unsaturated substrates (e.g., aromatic and olefinic C—H bonds substrates) are stronger than their aliphatic counterparts (BDE>110 kcal/mol), the available π-electron system provides a handle to engage the transition metal catalyst prior to C—H bond activation; furthermore, the C—H bonding orbitals are more exposed and thus exhibit greater reactivity. Although chemists have exploited these attributes en route to the functionalization of sp2 C—H bonds, where oxidative addition and reductive elimination reaction pathways are operative (Cho et al., Science 295, 305 (2002); Ishiyama et al., J. Am. Chem. Soc. 124, 390 (2002)), the catalytic conversion of sp3 C—H bonds within saturated hydrocarbon substrates to carbon-heteroatom bonds remains elusive.
Biological C—H bond functionalization is primarily performed by iron-containing enzymes that utilize dioxygen as the terminal oxidant. A key structural element of the putative hydroxylation catalyst in both heme (where iron is embedded in a porphyrin) and non-heme systems is a transiently formed terminal iron oxo species, typically thought to involve multiple bond character (iron-oxo) (Ortiz de Montellano; Ed. Cytochrome P450: Structure, Mechanism, and Biochemistry, 4th ed.; Kluwer Academic/Plenum Publishers: New York, 2005; Krebs et al., Acc. Chem. Res. 2007, 40, 484). The iron-oxo contains two electrons residing in Fe—O π* orbitals [Fe(dxz, dyz)-O(px, py)], which result in a weakened Fe—O bond vector possessing radical character, and thus renders the entire unit a reactive functionality. As a consequence of this electronic configuration, the iron-oxo can activate substrate aliphatic C—H bonds via an H-atom abstraction mechanism and thereby circumvent the orbital spatial restrictions that hinder oxidative addition pathways. Subsequent substrate functionalization results from recombination of the organic radical generated in the activation step with the open-shell iron-hydroxyl to produce an alcohol product with concomitant reduction of the iron species. Despite this mechanistic precedent (Groves et al., Biochem. Biophys. Res. Commun. 81, 154 (1978), viable catalysts fashioned with these design principles are only now being discovered. Furthermore, the reactivity of this intermediate is believed to be dictated by its electronic structure (Decker et al., J. Am. Chem. Soc. 2007, 129, 15938; Bernasconi et al., Eur. J. Inorg. Chem. 2007, 3023; Ye et al., Curr. Opin. Chem. Biol. 2009, 13, 89). In non-heme enzymes, four such FeIV (oxo) complexes have been characterized, and their reactivity has been linked to a common electronic feature: namely a high-spin ground state (S=2) (Krebs et al., Acc. Chem. Res. 2007, 40, 484).
The direct functionalization of C—H bonds based on a strategy exemplified by cytochrome P450 would be transformative in converting ubiquitous C—H bonds into functional group handles and would circumvent the traditional synthetic requirement for functional group exchange (King et al., Top. Organometallic Chem. 6, 205, (2004)). The electronic structure of the cytochrome P450 reactive iron-oxo intermediate can be, in principle, be replicated with any metal-ligand multiple bond (Nugent et al., Metal-Ligand Multiple Bonds; Wiley: New York, N.Y., 1988), and would constitute a general strategy for the conversion of unactivated C—H bonds into a variety of C-heteroatom bond products. Indeed, metal stabilized carbene and nitrene transfer has garnered significant interest using noble metal catalysts (Zalatan et al., Top. Curr. Chem. 292, 347 (2010); Au et al., J. Am. Chem. Soc. 121, 9120 (1999); Davies et al., Nature 451, 417 (2008)). In contrast, late, first row-transition metal complexes are potentially ideal catalyst candidates but have been less explored. Their high d-electron count and compressed ligand fields (compared to their second and third row analogues) favor population of metal-ligand antibonding orbitals leading to destabilization and reactivity akin to the cytochrome P450 iron-oxo intermediate (Badiei et al., Angew. Chem., Int. Ed. 47, 9961 (2008); Laskowski et al., J. Am. Chem. Soc. 133, 771 (2011); King et al., J. Am. Chem. Soc. 133, 4917 (2011); Lyaskovskyy et al., J. Am. Chem. Soc. 133, 12264 (2011); Wiese et al., J. Am. Chem. Soc. 134, 10114 (2012)).
Parallel to the work targeted at iron-mediated hydroxylation chemistry, C—H bond amination (Müller et al., Chem. Rev. 2003, 103, 2905; Davies et al., Angew. Chem., Int. Ed. 2005, 44, 3518; Halfen, Curr. Org. Chem. 2005, 9, 657; Cenini et al., Coord. Chem. Rev. 2006, 250, 1234. Davies et al., Nature 2008, 451, 417; Collet et al., Chem. Commun. 2009, 5061; Zalatan et al., J. Top. Curr. Chem. 2010, 292, 347) and olefin aziridination (Müller et al., Chem. Rev. 2003, 103, 2905; Halfen, Curr. Org. Chem. 2005, 9, 657; Tanner, Angew. Chem., Int. Ed. 1994, 33, 599; Osborn et al., Tetrahedron: Asymmetry 1997, 8, 1693; Sweeney, Chem. Soc. Rev. 2002, 31, 247) have been reported. The synthesis and characterization of Fe(imido) complexes as isoelectronic surrogates to Fe(oxo) functionalities have been targeted in the pursuit of effecting viable catalytic delivery of the nitrene functional unit to a C—H bond or olefinic substrates. Iron imido complexes have now been characterized in four oxidation states spanning a range of spin states (FeII, S=0 (Brown et al., J. Am. Chem. Soc. 2005, 127, 1913); FeIII, S=1/2, 1, 3/2 (Brown et al., J. Am. Chem. Soc. 2003, 125, 322; Betley et al., J. Am. Chem. Soc. 2003, 125, 10782; Bart et al., J. Am. Chem. Soc. 2006, 128, 5302; Lu et al., J. Am. Chem. Soc. 2007, 129, 4; Scepaniak et al., Angew. Chem., Int. Ed. 2009, 48, 3158; Cowley et al., Inorg. Chem. 2010, 49, 6172); FeIV, S=1; (Verma et al., J. Am. Chem. Soc. 2000, 122, 11013; Thomas et al., J. Am. Chem. Soc. 2006, 128, 4956; Nieto et al., J. Am. Chem. Soc. 2008, 130, 2716); Fe(V), S=1/2 (Ni et al., Chem. Commun. 2008, 6045)) and have been shown to engage in group transfer to carbon monoxide to produce isocyanates (Brown et al., J. Am. Chem. Soc. 2003, 125, 322; Cowley et al., Chem. Commun. 2009, 1760) and to isocyanides to produce carbodiimides (Cowley et al., Chem. Commun. 2009, 1760), undergo hydrogenation (Bart et al., J. Am. Chem. Soc. 2006, 128, 5302), and perform H atom abstraction from C—H bonds (Cowley et al., Inorg. Chim. Acta 2011, 369, 40-44; King et al, Inorg. Chem. 2009, 48, 2361).
For example, it has been recently reported that a catalytic C—H bond amination of toluene yields secondary benzylamines through a transiently formed, high-spin (S=2) iron imido complex (Scheme 1). See, e.g., King et al. (J. Am. Chem. Soc. 2011, 133, 4917-4923). Isolation and characterization of the reactive intermediate elucidated the unique electronic structure of its high-spin iron-bound imido radical, wherein a high-spin Fe(III) (S=5/2) is antiferromagnetically coupled to the imido radical (S=−1/2) to give a high-spin ground state. This electronic structure places significant radical character on both the FeN σ and π bond vectors, facilitating both radical H-atom abstraction and radical recombination pathways to proceed. Furthermore, the amination catalytic cycle remains in the quintet spin state (S=5/2), making each step of the catalytic cycle spin-allowed.

Also reported is the preparation of substituted aziridines through a catalytic C—H bond amination of styrene (Scheme 2). See, e.g., King et al. (J. Am. Chem. Soc. 2011, 133, 4917-4923).

Despite these efforts, a facile synthetic route to a wide range of functionalized amines (e.g., acyclic and cyclic secondary amines) is still in need.